Adjunctive Use of Apyrase to Fibrinolytic Therapy

描述(申请人提供)：急性心肌梗死是大多数工业化国家的主要死亡原因。美国的年发病率估计为865,000例，其中ST段抬高心肌梗死(STEMI，严重急性心肌梗死)每年约有500,000例。纤溶治疗因其广泛适用于广大患者而被广泛应用于恢复冠脉血流。目前的治疗方案，包括组织型纤溶酶原激活剂、阿司匹林、氯吡格雷和肝素，仍有30%~40%的患者冠状动脉再通不足，5%~10%的患者早期血栓再闭塞。此外，成功的再通会造成有害的再灌注损伤，占心肌梗死最终面积的50%。净临床不良结果在治疗后30天仍为10-12%，16-17%的STEMI患者在一年的随访中死亡。此外，围术期出血患者的发病率和死亡率都显著增加。重要的是，大多数复发性心肌梗塞和主要出血事件发生在治疗后的头几个小时和几天内。因此，寻找更有效、更安全、能有效减轻再灌注损伤的急性抗血栓药物仍是药物开发的“圣杯”。APT102是一种具有两个氨基酸取代的优化的人apyrase，其活性明显高于野生型apyrase。这种酶通过酶解细胞外的ADP和ATP来抑制血小板的激活和限制血管炎症。腺苷是由CD73进一步产生的，CD73可以在缺氧和心脏再灌注损伤时防止组织损伤。此外，APT102还可防止血小板脱敏并维持体内平衡。通过I期奖，我们证明了在r-tPA诱导的犬纤溶模型中，APT102的治疗完全防止了再闭塞，维持了正常的血流，并且与氯吡格雷相比，大大减少了心脏梗死面积的80%。同时，APT102不像氯吡格雷那样延长出血时间。这项第二阶段SBIR赠款申请的目标是严格确定在犬冠状动脉纤溶模型中，与氯吡格雷相比，APT102是否能在出血最少的情况下改善心肌灌注和左心功能。长期目标是开发APT102作为一种高效的抗血栓和抗炎疗法，并将出血风险降至最低，这将大大提高急性心肌梗死和其他血栓患者的急性治疗的有效性和安全性。 公共卫生相关性：这项第二阶段SBIR赠款申请的目标是严格确定在犬冠状动脉纤溶模型中，与氯吡格雷相比，APT102是否在出血最少的情况下促进心肌灌注和左心功能的改善。

DESCRIPTION (provided by applicant): Acute myocardial infarction is the leading cause of death in most industrialized nations. The estimated annual incidence in the US is 865,000 events, with ST-segment elevation myocardial infarction (STEMI, severe AMI) comprising an estimated 500,000 events per year. Fibrinolytic therapy is widely utilized to restore coronary blood flow due to its widespread availability to the broad cross-section of patients. The current regimen, including tissue plasminogen activator, aspirin, clopidogrel and heparin, still induces inadequate coronary reperfusion in 30-40% of patients and early thrombotic reocclusion in 5-10% patients. Moreover, successful recanalization causes detrimental reperfusion injury that accounts for up to 50% of the final size of a myocardial infarct. Net clinical adverse outcomes remain 10-12% at 30 days after treatment and 16-17% STEMI patients die during 1-year follow-up. Moreover, both morbidity and mortality are dramatically increased in patients experiencing peri-procedure bleeding. Importantly, most of the recurrent MI and major bleeding events occur in the first hours and days after treatment. Consequently, the search for more efficacious and safer acute antithrombotic agents with effective attenuation of reperfusion injury remains the "holy grail' of drug development. APT102 is an optimized human apyrase with two amino acid substitution that has significantly higher activity than the wild-type apyrases. This enzyme inhibits platelet activation and limits vascular inflammation by enzymatically hydrolyzing extracellular ADP and ATP. Adenosine is further generated by CD73 which prevents tissue damage during hypoxia and in the setting of cardiac reperfusion injury. In addition, APT102 prevents platelet desensitization and maintains homeostasis. With the Phase I award, we demonstrated that in the r-tPA induced fibrinolysis model in dogs, treatment of APT102 completely prevented re-occlusion, maintained normal blood flow, and profoundly reduced infarct size of hearts by 80% compared with clopidogrel. Meanwhile, APT102 did not prolong bleeding time, as did clopidogrel. The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel. The long-term goal is to develop APT102 as a highly effective antithrombotic and anti-inflammatory therapy with minimal bleeding risk that will profoundly improve efficacy and safety of acute treatment for AMI and other thrombotic patients. PUBLIC HEALTH RELEVANCE: The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel.